Download Manganese Bulletin

This is an excerpted article from the following website:
http://lpi.oregonstate.edu/infocenter/minerals/manganese/
The first part of this article is quite technical but if you scroll through the
document you will find quite a few interesting sections that are not in technical
jargon.
At the end of this article I have referenced two other websites that may be of
interest.
Manganese
Manganese is a mineral element that is both nutritionally essential and potentially toxic. The
derivation of its name from the Greek word for magic remains appropriate, because scientists are
still working to understand the diverse effects of manganese deficiency and manganese toxicity
in living organisms.
Function
Manganese (Mn) plays an important role in a number of physiologic processes as a constituent of
multiple enzymes and an activator of other enzyme.
Antioxidant function
Manganese superoxide dismutase (MnSOD) is the principal antioxidant enzyme in the
mitochondria. Because mitochondria consume over 90% of the oxygen used by cells, they are
especially vulnerable to oxidative stress. The superoxide radical is one of the reactive oxygen
species produced in mitochondria during ATP synthesis. MnSOD catalyzes the conversion of
superoxide radicals to hydrogen peroxide, which can be reduced to water by other antioxidant
enzyme.
Metabolism
A number of manganese-activated enzymes play important roles in the metabolism of
carbohydrates, amino acids, and cholesterol. Pyruvate carboxylase, a manganese-containing
enzyme, and phosphoenolpyruvate carboxykinase (PEPCK), a manganese-activated enzyme, are
critical in gluconeogenesis— the production of glucose from non-carbohydrate
precursors. Arginase, another manganese-containing enzyme, is required by the liver for the urea
cycle, a process that detoxifies ammonia generated during amino acid metabolis. In the brain, the
manganese-activated enzyme, glutamine synthetase, converts the amino acid glutamate to
glutamine. Glutamate is an excitotoxic neurotransmitter and a precursor to an inhibitory
neurotransmitter, gamma-aminobutyric acid (GABA).
Bone development
Manganese deficiency results in abnormal skeletal development in a number of animal species.
Manganese is the preferred cofactor of enzymes called glycosyltransferases; these enzymes are
required for the synthesis of proteoglycans that are needed for the formation of healthy cartilage
and bone.
Wound healing
Wound healing is a complex process that requires increased production of collagen. Manganese
is required for the activation of prolidase, an enzyme that functions to provide the amino acid,
proline, for collagen formation in human skin cells. A genetic disorder known as prolidase
deficiency results in abnormal wound healing among other problems, and is characterized by
abnormal manganese metabolism. Glycosaminoglycan synthesis, which requires manganeseactivated glycosyltransferases, may also play an important role in wound healing.
Nutrient interactions
Iron
Although the specific mechanisms for manganese absorption and transport have not been
determined, some evidence suggests that iron and manganese can share common absorption and
transport pathways. Absorption of manganese from a meal decreases as the meal's iron content
increases. Iron supplementation (60 mg/day for four months) was associated with decreased
blood manganese levels and decreased MnSOD activity in white blood cells, indicating a
reduction in manganese nutritional status. Additionally, an individual's iron status can affect
manganese bioavailability. Intestinal absorption of manganese is increased during iron
deficiency, and increased iron stores (ferritin levels) are associated with decreased manganese
absorption. Men generally absorb less manganese than women; this may be related to the fact
that men usually have higher iron stores than women. Further, iron deficiency has been shown to
increase the risk of manganese accumulation in the brain.
Magnesium
Supplemental magnesium (200 mg/day) has been shown to slightly decrease manganese
bioavailability in healthy adults, either by decreasing manganese absorption or by increasing its
excretion.
Calcium
In one set of studies, supplemental calcium (500 mg/day) slightly decreased manganese
bioavailability in healthy adults. As a source of calcium, milk had the least effect, while calcium
carbonate and calcium phosphate had the greatest effect. Several other studies have found
minimal effects of supplemental calcium on manganese metabolism.
Deficiency
Manganese deficiency has been observed in a number of animal species. Signs of manganese
deficiency include impaired growth, impaired reproductive function, skeletal abnormalities,
impaired glucose tolerance, and altered carbohydrate and lipid metabolism. In humans,
demonstration of a manganese deficiency syndrome has been less clear. A child on long-term
total parenteral nutrition (TPN) lacking manganese developed bone demineralization and
impaired growth that were corrected by manganese supplementation. Young men who were fed a
low-manganese diet developed decreased serum cholesterol levels and a transient skin rash.
Blood calcium, phosphorus, and alkaline phosphatase levels were also elevated, which may
indicate increased bone remodeling as a consequence of insufficient dietary manganese. Young
women fed a manganese-poor diet developed mildly abnormal glucose tolerance in response to
an intravenous (IV) infusion of glucose. Overall, manganese deficiency is not common, and there
is more concern for toxicity related to manganese overexposure (see Safety).
The Adequate Intake (AI)
Because there was insufficient information on manganese requirements to set a Recommended
Dietary Allowance (RDA), the Food and Nutrition Board (FNB) of the Institute of Medicine set
an adequate intake level (AI). Since overt manganese deficiency has not been documented in
humans eating natural diets, the FNB based the AI on average dietary intakes of manganese
determined by the Total Diet Study—an annual survey of the mineral content of representative
American diets. AI values for manganese are listed in the table below in milligrams (mg)/day by
age and gender. Manganese requirements are increased in pregnancy and lactation.
Adequate Intake (AI) for Manganese
Males
(mg/day)
Females
(mg/day)
0-6 months
0.003
0.003
Infants
7-12 months
0.6
0.6
Children
1-3 years
1.2
1.2
Children
4-8 years
1.5
1.5
Children
9-13 years
1.9
1.6
Adolescents
14-18 years
2.2
1.6
Adults
19 years and older
2.3
1.8
Pregnancy
all ages
-
2.0
Breast-feeding
all ages
-
2.6
Life Stage
Age
Infants
Disease Prevention
Low dietary manganese or low levels of manganese in blood or tissue have been associated with
several chronic diseases. Although manganese insufficiency is not currently thought to cause the
diseases discussed below, more research may be warranted to determine whether suboptimal
manganese nutritional status contributes to certain disease processes.
Osteoporosis
Women with osteoporosis have been found to have decreased plasma or serum levels of
manganese and also an enhanced plasma response to an oral dose of manganese, suggesting they
may have lower manganese status than women without osteoporosis. Yet, a more recent study in
postmenpausal women with and without osteoporosis did not find any differences in plasma
levels of manganese. A study in healthy postmenopausal women found that a supplement
containing manganese (5 mg/day), copper (2.5 mg/day), and zinc (15 mg/day) in combination
with a calcium supplement (1,000 mg/day) was more effective than the calcium supplement
alone in preventing spinal bone loss over a two-year period. However, the presence of other trace
elements in the supplement makes it impossible to determine whether manganese
supplementation was the beneficial agent for maintaining bone mineral density.
Diabetes mellitus
Manganese deficiency results in glucose intolerance similar to diabetes mellitus in some animal
species, but studies examining the manganese status of diabetic humans have generated mixed
results. In one study, whole blood manganese levels did not differ significantly between 57
diabetics and 28 non-diabetic controls. However, urinary manganese excretion tended to be
slightly higher in 185 diabetics compared to 185 non-diabetic controls. A case-control study of
250 diabetic and non-diabetic individuals found that type 2 diabetic individuals had higher serum
manganese levels than non-diabetics. However, a more recent study in 257 type 2 diabetics and
166 non-diabetic controls found lower blood levels of manganese in the diabetic patients.
Additionally, a study of functional manganese status found the activity of the antioxidant
enzyme, MnSOD, was lower in the white blood cells of diabetics than in non-diabetics. Neither
15 mg nor 30 mg of oral manganese improved glucose tolerance in diabetics or non-diabetic
controls when given at the same time as an oral glucose challenge. Although manganese appears
to play a role in glucose metabolism, there is little evidence that manganese supplementation
improves glucose tolerance in diabetic or non-diabetic individuals.
Epilepsy (seizure disorders)
Manganese deficient rats are more susceptible to seizures than manganese sufficient rats, and rats
that are genetically prone to epilepsy have lower than normal brain and blood manganese levels.
Certain subgroups of humans with epilepsy reportedly have lower whole blood manganese levels
than non-epileptic controls. One study found blood manganese levels of individuals with
epilepsy of unknown origin were lower than those of individuals whose epilepsy was induced by
trauma (e.g., head injury) or disease, suggesting a possible genetic relationship between epilepsy
and abnormal manganese metabolism. While manganese deficiency does not appear to be a
cause of epilepsy in humans, the relationship between manganese metabolism and epilepsy
deserves further research.
Sources
Food sources
In the U.S., estimated average dietary manganese intakes range from 2.1-2.3 mg/day for men and
1.6-1.8 mg/day for women. People eating vegetarian diets and Western-type diets may have
manganese intakes as high as 10.9 mg/day. Rich sources of manganese include whole grains,
nuts, leafy vegetables, and teas. Foods high in phytic acid, such as beans, seeds, nuts, whole
grains, and soy products, or foods high in oxalic acid, such as cabbage, spinach, and sweet
potatoes, may slightly inhibit manganese absorption. Although teas are rich sources of
manganese, the tannins present in tea may moderately reduce the absorption of manganese.
Intake of other minerals, including iron, calcium, and phosphorus, have been found to limit
retention of manganese. The manganese content of some manganese-rich foods is listed in
milligrams (mg) in the table below. For more information on the nutrient content of foods, search
the USDA food composition database.
Food
Serving
Pineapple, raw
Pineapple juice
Pecans
Almonds
Peanuts
Instant oatmeal (prepared with water)
Raisin bran cereal
Brown rice, cooked
Whole wheat bread
Pinto beans, cooked
Lima beans, cooked
Navy beans, cooked
Spinach, cooked
Sweet potato, cooked
Tea (green)
Tea (black)
1/2 cup, chunks
1/2 cup (4 fl. oz.)
1 ounce (19 halves)
1 ounce (23 whole kernels)
1 ounce
1 packet
1 cup
1/2 cup
1 slice
1/2 cup
1/2 cup
1/2 cup
1/2 cup
1/2 cup, mashed
1 cup (8 ounces)
1 cup (8 ounces)
Manganese
(mg)
0.77
0.63
1.28
0.65
0.55
0.99
0.78-3.02
1.07
0.60
0.39
0.49
0.48
0.84
0.44
0.41-1.58
0.18-0.77
Breast Milk and Infant Formulas
Infants are exposed to varying amounts of manganese depending on their source of nutrition.
Manganese concentrations in breast milk, cow-based formula, and soy-based formula range from
3-10 mcg/liter, 30-50 mcg/liter, and 200-300 mcg/liter, respectively. However, bioavailability of
manganese from breast milk is higher than from infant formulas, and manganese deficiencies in
breast-fed infants or toxicities in formula-fed infants have not been reported.
Water
Manganese concentrations in drinking water range from 1 to 100 micrograms (mcg)/liter, but
most sources contain less than 10 mcg/liter. The U.S. Environmental Protection Agency (EPA)
recommends 0.05 mg (50 mcg)/liter as the maximum allowable manganese concentration in
drinking water.
Supplements
Several forms of manganese are found in supplements, including manganese gluconate,
manganese sulfate, manganese ascorbate, and amino acid chelates of manganese. Manganese is
available as a stand-alone supplement or in combination products. Relatively high levels of
manganese ascorbate may be found in a bone/joint health product containing chondroitin sulfate
and glucosamine hydrochloride (see Safety).
Safety
Toxicity
Inhaled manganese
Manganese toxicity may result in multiple neurologic problems and is a well-recognized health
hazard for people who inhale manganese dust, such as welders and smelters. Unlike ingested
manganese, inhaled manganese is transported directly to the brain before it can be metabolized in
the liver. The symptoms of manganese toxicity generally appear slowly over a period of months
to years. In its worst form, manganese toxicity can result in a permanent neurological disorder
with symptoms similar to those of Parkinson's disease, including tremors, difficulty walking, and
facial muscle spasms. This syndrome, often called manganism, is sometimes preceded by
psychiatric symptoms, such as irritability, aggressiveness, and even hallucinations. Additionally,
environmental or occupational inhalation of manganese can cause an inflammatory response in
the lungs. Clinical symptoms of effects to the lung include cough, acute bronchitis, and
decreased lung function.
Methylcyclopentadienyl manganese tricarbonyl (MMT)
MMT is a manganese-containing compound used in gasoline as an anti-knock additive. Although
it has been used for this purpose in Canada for more than 20 years, uncertainty about adverse
health effects from inhaled exhaust emissions kept the U.S. EPA from approving its use in
unleaded gasoline. In 1995, a U.S. court decision made MMT available for widespread use in
unleaded gasoline. A study in Montreal, where MMT had been used for more than ten years,
found airborne manganese levels to be similar to those in areas where MMT was not used. A
more recent Canadian study found higher concentrations of respirable manganese in an urban
versus a rural area, but average concentrations in both areas were below the safe level set by the
U.S. EPA. The impact of long-term exposure to low levels of MMT combustion products,
however, has not been thoroughly evaluated and will require additional study.
Ingested manganese
Limited evidence suggests that high manganese intakes from drinking water may be associated
with neurological symptoms similar to those of Parkinson's disease. Severe neurological
symptoms were reported in 25 people who drank water contaminated with manganese, and
probably other contaminants, from dry cell batteries for two to three months. Water manganese
levels were found to be 14 mg/liter almost two months after symptoms began and may have
already been declining. A study of older adults in Greece found a high prevalence of
neurological symptoms in those exposed to water manganese levels of 1.8-2.3 mg/liter, while a
study in Germany found no evidence of increased neurological symptoms in people drinking
water with manganese levels ranging from 0.3-2.2 mg/liter compared to those drinking water
containing less than 0.05 mg/liter. Manganese in drinking water may be more bioavailable than
manganese in food. However, none of the studies measured dietary manganese, so total
manganese intake in these cases is unknown. In the U.S., the EPA recommends 0.05 mg/liter as
the maximum allowable manganese concentration in drinking water.
Additionally, more recent studies have shown that children exposed to high levels of manganese
through drinking water experience cognitive and behavioral deficits. For instance, a crosssectional study in 142 10-year old children, who were exposed to a mean manganese water
concentration of 0.8 mg/liter, found that children exposed to higher manganese levels had
significantly lower scores on three tests of intellectual function. Another study associated high
levels of manganese in tap water with hyperactive behavioral disorders in children. These and
other recent reports have raised concern over the neurobehavioral effects of manganese exposure
in children.
A single case of manganese toxicity was reported in a person who took large amounts of mineral
supplements for years, while another case was reported as a result of a person taking a Chinese
herbal supplement. Manganese toxicity resulting from foods alone has not been reported in
humans, even though certain vegetarian diets could provide up to 20 mg/day of manganese.
Intravenous manganese
Manganese neurotoxicity has been observed in individuals receiving total parenteral nutrition,
both as a result of excessive manganese in the solution and as an incidental contaminant.
Neonates are especially vulnerable to manganese-related neurotoxicity. Infants receiving
manganese-containing TPN can be exposed to manganese concentrations about 100-fold higher
than breast-fed infants. Because of potential toxicities, some argue against including manganese
in parenteral nutrition.
Individuals with increased susceptibility to manganese toxicity




Chronic liver disease: Manganese is eliminated from the body mainly in bile. Thus,
impaired liver function may lead to decreased manganese excretion. Manganese
accumulation in individuals with cirrhosis or liver failure may contribute to neurological
problems and Parkinson's disease-like symptoms.
Newborns: The newborn brain may be more susceptible to manganese toxicity due to a
greater expression of receptors for the manganese transport protein (transferrin) in
developing nerve cells and the immaturity of the liver's bile elimination system.
Children: Compared to adults, infants and children have higher intestinal absorption of
manganese, as well as lower biliary excretion of manganese. Thus, children are especially
susceptible to any negative, neurotoxic effects of manganese. Indeed, several recent
studies in school-aged children have reported deleterious cognitive and behavioral effects
following excessive manganese exposure.
Iron-deficient populations: Iron deficiency has been shown to increase the risk of
manganese accumulation in the brain.
Due to the severe implications of manganese neurotoxicity, the Food and Nutrition Board (FNB)
of the Institute of Medicine set very conservative tolerable upper intake levels (UL) for
manganese; the ULs are listed in the table below according to age.
Tolerable Upper Intake Level (UL) for Manganese
Age Group
UL (mg/day)
Infants 0-12 months
Not possible to establish*
Children 1-3 years
2
Children 4-8 years
3
Children 9-13 years
6
Adolescents 14-18 years
9
Adults 19 years and older
11
*Source of intake should be from food and formula only.
Drug interactions
Magnesium-containing antacids and laxatives and the antibiotic medication, tetracycline, may
decrease the absorption of manganese if taken together with manganese-containing foods or
supplements.
High levels of manganese in supplements marketed for bone/joint health
Two studies have found that supplements containing a combination of glucosamine
hydrochloride, chondroitin sulfate, and manganese ascorbate are beneficial in relieving pain due
to mild or moderate osteoarthritis of the knee when compared to a placebo. The dose of
elemental manganese supplied by the supplements was 30 mg/day for eight weeks in one study
and 40 mg/day for six months in the other. No adverse effects were reported during either study,
and blood manganese levels were not measured. Neither study compared the treatment
containing manganese ascorbate to a treatment containing glucosamine hydrochloride and
chondroitin sulfate without manganese ascorbate, so it is impossible to determine whether the
supplement would have resulted in the same benefit without high doses of manganese.
Linus Pauling Institute Recommendation
The adequate intake (AI) for manganese (2.3 mg/day for adult men and 1.8 mg/day for adult
women) appears sufficient to prevent deficiency in most individuals. The daily intake of
manganese most likely to promote optimum health is not known. Following the Linus Pauling
Institute recommendation to take a multivitamin/multimineral supplement containing 100% of
the daily values (DV) of most nutrients will generally provide 2 mg/day of manganese in
addition to that in foods. Because of the potential for toxicity and the lack of information
regarding benefit, manganese supplementation beyond 100% of the DV (2 mg/day) is not
recommended. There is presently no evidence that the consumption of a manganese-rich plantbased diet results in manganese toxicity.
Older adults (> 50 years)
The requirement for manganese is not known to be higher for older adults. However, liver
disease is more common in older adults and may increase the risk of manganese toxicity by
decreasing the elimination of manganese from the body (see Toxicity). Manganese
supplementation beyond 100% of the DV (2 mg/day) is not recommended.
References
Written in August 2001 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in March 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in March 2010 by:
Michael Aschner, Ph.D.
Chair, Department of Nutrition
Gray E.B. Stahlman Professor of Neuroscience
Professor of Pediatrics
Professor of Pharmacology
Vanderbilt University Medical Center
Copyright 2001-2014 Linus Pauling Institute
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on
the health aspects of dietary factors and supplements, foods, and beverages for the general
public. The information is made available with the understanding that the author and publisher
are not providing medical, psychological, or nutritional counseling services on this site. The
information should not be used in place of a consultation with a competent health care or
nutrition professional.
The information on dietary factors and supplements, foods, and beverages contained on this Web
site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not
intended as nutritional or medical advice for individual problems. Liability for individual actions
or omissions based upon the contents of this site is expressly disclaimed.
Another interesting website is:
http://www.whfoods.com/genpage.php?tname=nutrient&dbid=77
This site is slanted towards the foods it promotes.
A National Institute of Health article on Manganese supplements is at:
http://www.nlm.nih.gov/medlineplus/druginfo/natural/182.html